A Novel Asymmetric Benzoin Reaction Catalyzed by a Chiral Triazolium Salt. Preliminary communication

Abstract

Using the chiral triazolium salt 1 as catalyst, a novel asymmetric variant of the benzoin reaction is reported. For the first time, the scope of the method is extended to a broader range of aromatic aldehydes 2, affording the acyloins 3a-h in yields of 22-72% and enantiomeric excesses up to 86%.

The enantioselective benzoin condensation promoted by chiral triazolium precatalysts: stereochemical control via hydrogen bonding

“…Enders et al 16 have reported that carbenes derived from triazolium ions devoid of substitution at C-3 are less stable catalysts than their C-3 substituted analogues. In order to probe this, we also synthesised the achiral catalysts 28 and 29 from cyclohexyl amine (30) and diazolium salts 25 and 31(Scheme 5)-addition of the amine to the diazolium salts furnished isolable adducts 32 and 33, which could then be slowly cyclised 29 in acetonitrile at reflux temperature to give the novel triazolium salts 28 and 29 in good yields.…”

“…The compatibility of other simple bases with the methodology was then evaluated: at 4 mol% catalyst loading (3.2 mol% base) Li 2 CO 3 , Na 2 CO 3 and NaHCO 3 proved completely ineffective (entries 10-12), while KHCO 3 and K 2 CO 3 furnished promising product yields of 32 and 42%, respectively, under identical conditions (entries 13 and 14). Optimisation of the loading of both catalyst and base using K 2 CO 3 led to conditions under which 6 could be obtained in up to 58% yield (entries [14][15][16][17][18][19][20]; however, this methodology was unsatisfactory due to a difficulty in arriving at a system of acceptable reproducibility (i.e. <5% discrepancy in yield between runs), despite considerable experimentation (>150 iterative runs) and the rigorous exclusion of air, moisture, etc.…”

Computational predictions of stereochemistry in asymmetric thiazolium- and triazolium-catalyzed benzoin condensations

“…The highest recorded enantiomeric excess (ee) for a thiazolium-catalyzed benzoin condensation (51% ee) was reported by Sheehan et al (10), using the chiral catalyst (S)-(Ϫ)-4-methyl-3-␣-(1-napthyl)ethylthiazolium tetrafluoroborate that afforded the product in only 6% yield. Chiral triazolium salts have fared better (5,11,12). For example, the chemically robust triazolium catalyst 1 recently prepared by Enders et al (11) affords benzoin products in high yields with enantiomeric excesses as high as 95% (Eq.…”

From Mono‐Triazolium Salt to Bis‐Triazolium Salt: Improvement of the Asymmetric Intermolecular Benzoin Condensation

“…[3] Finally in 1996, Enders et al broke the ice using a chiral triazolium salt as precatalyst for the enantioselective benzoin reaction, which was able to be extended for the first time to a variety of aromatic aldehydes in 22-72% yields with ee values of 20-86%. [4] Later, Leeper et al developed bicyclic chiral triazolium salts and documented their application to the benzoin condensation with comparable enantioselectivities (yields: 11-50%, 20-82.5% ee), [5] which were further improved by Enders et al with another bicyclic chiral triazolium salt. [6] The acyloin product from benzaldehyde was isolated in 83% yield with 90% ee, which was the highest value recorded for a non-enzyme-dependent, catalyzed benzoin reaction in terms of chemical yield and enantioselection.…”

“…[10] Furthermore, these results have demonstrated that it is difficult to improve this type of asymmetric reaction by increasing the loadings of triazolium precatalyst because the higher concentration of bicyclic triazolylidene with its characteristic basic properties could lead to a partial racemization of acyloin product. [4][5][6][7] Clearly, one of the key issues to overcome this problem is to develop a class of chiral triazolylidene catalysts that display high catalytic activity with essentially low catalyst loadings, minimizing a racemization of acyloins. However, in the last six years the challenging enantioselective intermolecular benzoin reactions met with limited success although a series of chiral triazolium salts annulated by aliphatic cyclic skeletons were prepared using a modification of Knight and Leepers synthesis [10g,11] and exhibited remarkable umpolung asymmetric organocatalysis.…”